Project Summary/Abstract This application proposes a training program to integrate the PI, Dr. Varadan's previous research efforts in informatics and machine learning into investigations pertaining to the etiology and progression of Barrett's Esophagus, a gastrointestinal disorder of significant public health interest. Much of Dr. Varadan's previous research has involved developing intelligent algorithms and informatics approaches to decode the interconnections within complex biological systems, with only a basic understanding of the clinical needs and complexities involved in translational research. The proposed project would provide a broad and in-depth mentored experience focused on clinical and biological aspects of Barrett's Esophagus, as well as added knowledge in the use of preclinical model systems to investigate biological mechanisms. The overall goal is to expand the PI's experience and training in the design and conduct of translational studies focused on gastrointestinal (GI) diseases. This objective will be achieved through a combination of didactic and research activities conducted under an exceptional mentoring team of translational researchers at Case Western Reserve University, spanning achievements across clinical management of GI disorders, molecular genetics and inflammatory processes associated with diseases of the gut. Accordingly, this proposal leverages Dr. Varadan's computational background to address an urgent and unmet need within the biomedical research community to develop reliable analytic approaches that can quantify signaling network activities in individual biological samples by integrating multi-omics measurements. We recently conceived a systems biology computational framework, InFlo, which integrates molecular profiling data to decode the functional states of cellular/molecular processes underpinning complex human diseases. Barrett's esophagus is one such complex disease gaining increasing importance to public health, as it is the known precursor to the deadly cancer, esophageal adenocarcinoma. Given that the mechanisms underlying the etiology and pathogenesis of Barrett's Esophagus remain elusive, a major objective of this proposal is to employ the InFlo framework combined molecular profiles derived from primary tissue cohorts, in vitro and in vivo model systems to establish the molecular roadmap of BE pathogenesis and disease recurrence, thus elucidating unifying mechanisms underlying this disease. This systems biology approach would enable the development of evidence-based, diagnostic/prognostic biomarkers for Barrett's esophagus and inform preventive strategies within at-risk populations.